Biology subjects

Bonnefont, J.

Publications and source records attributed to Bonnefont, J..

4 recordsLinked to original sources

bioRxiv2022

Histone H2A monoubiquitination in the thalamus regulates cocaine effects and addiction risk

The individual risk of developing drug addiction is highly determined by the epigenetic landscape1,2. Chromatin remodeling regulates drug-induced transcriptional and behavioral effects and the consequent development of addictive behaviors2,3. Several chromatin modifications in the ventral tegmental area and nucleus accumbens, including histone H3 methylation, H3 and H4 acetylation, have been implicated in drug addiction. Still, the contribution of other histones and their post-translational modifications (PTMs), such as monoubiquitination is unclear4-8. In the course of investigating the underlying mechanisms associated with melanoma-associated antigen D1 (Maged1)9, a scaffold protein involved in drug addiction9, we found that H2A monoubiquitination in the paraventricular thalamus (PVT) plays a major role in cocaine-adaptive behaviors and cocaine-evoked transcriptional repression. Mice undergoing chronic cocaine administration showed a significant increased monoubiquitination of H2A. Furthermore, we showed that this histone PTM is controlled, in the PVT, by Maged1, along with one of its partner, the deubiquitinase USP710. Accordingly, Maged1 specific inactivation in thalamic vGluT2 neurons, or USP7 inhibition, blocked cocaine-evoked H2A monoubiquitination and abolished cocaine locomotor sensitization. Finally, we identified genetic variations of MAGED1 and USP7 associated with modified transition to cocaine addiction and cocaine-induced aggressive behavior in human subjects. These findings identified a new epigenetic modification in a non-canonical reward pathway of the brain and a potent marker of epigenetic risk factor for drug addiction in human.

neuroscience↗

bioRxiv2021

Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6-dependent pathway

Developmental neuron death plays a pivotal role in refining organization and wiring during neocortex formation. Aberrant regulation of this process results in neurodevelopmental disorders including impaired learning and memory. Underlying molecular pathways are incompletely determined. Loss of Bcl11a in cortical projection neurons induces pronounced cell death in upper-layer cortical projection neurons during postnatal corticogenesis. We used this genetic model to explore genetic mechanisms by which developmental neuron death is controlled. Unexpectedly, we found Bcl6, previously shown to be involved in transition of cortical neurons from progenitor to postmitotic differentiation state to provide a major check point regulating neuron survival during late cortical development. We show that Bcl11a is a direct transcriptional regulator of Bcl6. Deletion of Bcl6 exerts death of cortical projection neurons. In turn, reintroduction of Bcl6 into Bcl11a mutants prevents induction of cell death in these neurons. Together, our data identify a novel Bcl11a/Bcl6-dependent molecular pathway in regulation of developmental cell death during corticogenesis.

neuroscience↗

bioRxiv2020

CROCCP2 acts as a human-specific modifier of cilia dynamics and mTOR signalling to promote expansion of cortical progenitors.

The primary cilum is a central component of signalling during neural development, from regional patterning to neuronal differentiation. Here we focus on CROCCP2, a hominid-specific gene duplicate from CROCC (Ciliary Rootlet Coiled Coil), also known as rootletin, that encodes the major protein component of the ciliary rootlet. We find that CROCCP2 is highly expressed in the human fetal brain and not in other primate species. CROCCP2 gain of function in the mouse embryonic cortex results in decreased ciliogenesis, increased mTOR signalling, and increased cell size of radial glial cells, leading to increased generation of intermediate/basal progenitors and increased neuronal output. CROCCP2 impacts cilia dynamics and neurogenesis by inhibition of the IFT20 ciliary trafficking protein. Our data identify a human-specific protein that drives cortical basal progenitor expansion through modulation of ciliary dynamics.

neuroscience↗

bioRxiv2018

Bcl6 promotes neurogenic conversion through transcriptional repression of multiple self-renewal-promoting extrinsic pathways.

During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here we combine whole genome transcriptional and epigenetic analyses with in vivo functional studies and show that Bcl6, a transcriptional repressor known to promote neurogenesis, acts as a key driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 acts through both generic and pathway-specific mechanisms. Our data identify a molecular logic by which a single cell-intrinsic factor ensures robustness of neural cell fate transition by decreasing responsiveness to the extrinsic pathways that favor self-renewal.

neuroscience↗